Why is hypercalciuria absent at diagnosis in some children with ATP6V1B1 mutation?

Abstract

We try to explain why hypercalciuria is absent at diagnosis in some children with an ATP6V1B1 mutation. A 5-month-old girl presented with distal renal tubular acidosis (dRTA) and sensorineural hearing loss. Direct sequencing of the ATP6V1B1 genes disclosed a new homozygous mutation (452 delT) in exon 13. In particular, an absence of hypercalciuria and a normal level of parathyroid hormones were noted. After alkaline therapy, the signs of nephrocalcinosis improved on ultrasound during follow-up. After a review of the literature regarding patients with ATP6V1B1 gene mutations, a young age seemed to be an important factor for normocalciuria. The probable mechanism of normocalciuria and a dynamic mode of calcium excretion in patients with dRTA is proposed. The determinant factors include the degree of systemic acidosis, urine pH, genetic polymorphisms, age, dietary factors, and volume status. Low sodium intake may be a major determinant of normocalciuria in these patients. It is suggested that hypercalciuria is usually absent at diagnosis of dRTA in young infants. Blood pH, plasma bicarbonate concentration, urinary citrate levels, and growth catch-up may be better indicators of adequate alkali therapy in normocalciuric children. Volume contraction, low salt content in infant formula, and alkaline urine in young infants are likely to account for the increased calcium reabsorption.

Mutation analysis and audiologic assessment in six Chinese children with primary distal renal tubular acidosis

“…In fact, normocalciuria is not uncommon at diagnosis in young dRTA patients (51 year). 4,14,15 As we all know, many factors can contribute to the differences in urinary calcium excretion, such as dietary, calcium absorption and hormonal control, as well as renal handling of calcium. Three (patient I-1, II-1 and IV-1) of the four patients with normocalciuria had evident signs of dehydration resulted by vomiting, fever, or other causes at diagnosis in this study.…”

“…Low salt intake is associated with decreased urinary calcium excretion. 15,16 All these children were diagnosed before the age of 6 months. As we know, breast milk or infant formula, which has relatively low sodium content, is the principal source of calories for them at this stage.…”

“…As we know, breast milk or infant formula, which has relatively low sodium content, is the principal source of calories for them at this stage. 15 Therefore, we suppose that low dietary salt intake may help to explain their normal urinary calcium excretion. Furthermore, dietary sodium restriction may aggravate volume depletion and augment hypocalciuria.…”

“…Tsai HY et al proposed a dynamic mode of calcium excretion in patients with dRTA which well explained this ambivalence. 15 At the early stage, metabolic acidosis promotes bone demineralization and hypercalciuria. 17 Hypercalciuria, persistently high urine pH and profound hypocitraturia predispose the development of the nephrocalcinosis.…”

Acidosis and Urinary Calcium Excretion: Insights from Genetic Disorders

“…5 However, genetic diseases causing renal tubular acidosis vary with regard to increased calcium excretion and sequelae resulting from excessive urinary calcium losses, such as nephrocalcinosis and nephrolithiasis. 8,9 In this review, we will first briefly summarize over 90 years of experiments examining the relationship between acidosis and urinary calcium excretion. We will then highlight selected genetic disorders of altered acid-base balance, using them to understand why a direct coupling between acidosis and renal calcium losses and their associated sequelae are not consistently observed.…”